Second messenger function and the structure-activity relationship of cyclic adenosine diphosphoribose (cADPR)

FEBS J. 2005 Sep;272(18):4590-7. doi: 10.1111/j.1742-4658.2005.04863.x.


Cyclic ADP-ribose (cADPR) is a Ca2+ mobilizing second messenger found in various cell types, tissues and organisms. Receptor-mediated formation of cADPR may proceed via transmembrane shuttling of the substrate NAD and involvement of the ectoenzyme CD38, or via so far unidentified ADP-ribosyl cyclases located within the cytosol or in internal membranes. cADPR activates intracellular Ca2+ release via type 2 and 3 ryanodine receptors. The exact molecular mechanism, however, remains to be elucidated. Possibilities are the direct binding of cADPR to the ryanodine receptor or binding via a separate cADPR binding protein. In addition to Ca2+ release, cADPR also evokes Ca2+ entry. The underlying mechanism(s) may comprise activation of capacitative Ca2+ entry and/or activation of the cation channel TRPM2 in conjunction with adenosine diphosphoribose. The development of novel cADPR analogues revealed new insights into the structure-activity relationship. Substitution of either the northern ribose or both the northern and southern ribose resulted in much simpler molecules, which still retained significant biological activity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium Signaling
  • Clusterin
  • Cyclic ADP-Ribose / chemistry
  • Cyclic ADP-Ribose / metabolism
  • Cyclic ADP-Ribose / physiology*
  • Glycoproteins / metabolism
  • Humans
  • Molecular Chaperones / metabolism
  • Ryanodine Receptor Calcium Release Channel / metabolism
  • Second Messenger Systems / physiology*
  • Structure-Activity Relationship


  • CLU protein, human
  • Clusterin
  • Glycoproteins
  • Molecular Chaperones
  • Ryanodine Receptor Calcium Release Channel
  • Cyclic ADP-Ribose
  • Calcium